Delivery of diazepam through an inhalation route

ABSTRACT

The present invention relates to the delivery of compounds for the treatment of anxiety disorders and symptoms of such disorders through an inhalation route. Specifically, it relates to aerosols containing diazepam that are used in inhalation therapy. In a method aspect of the present invention, diazepam is administered to a patient through an inhalation route. The method comprises: a) heating a thin layer of diazepam on a solid support to form a vapor; and, b) passing air through the heated vapor to produce aerosol particles having less than 5% drug degradation products. In a kit aspect of the present invention, a kit for delivering diazepam through an inhalation route is provided which comprises: a) a thin coating of a diazepam composition; and, b) a device for dispending said thin coating as a condensation aerosol.

[0001] This application is a continuation of U.S. patent applicationSer. No. 10/150,056, entitled “Delivery of Diazepam Through anInhalation Route,” filed May 15, 2002, Rabinowitz, and Zaffaroni; whichclaims priority to U.S. provisional application Ser. No. 60/345,882entitled “Delivery of Diazepam Through an Inhalation Route,” filed Nov.9, 2001, Rabinowitz, the entire disclosure of which is herebyincorporated by reference.

FIELD OF THE INVENTION

[0002] The present invention relates to the delivery of diazepam throughan inhalation route. Specifically, it relates to aerosols containingdiazepam that are used in inhalation therapy.

BACKGROUND OF THE INVENTION

[0003] VALIUM® is a composition currently marketed for the management ofanxiety disorders and the relief of anxiety symptoms. It is administeredboth orally and by injection. The active ingredient in VALIUM® isdiazepam, which is typically provided in doses of 2 mg to 20 mg.

[0004] The delivery methods for diazepam have a number of limitations.Oral administration typically provides for a relatively long onset ofaction (e.g. ≧1 h). Intravenous injection, while rapidly delivering adrug, involves the discomfort and risk of infection associated withcatheterization or injection. It is desirable to provide a new route ofadministration for diazepam that allows for a rapid onset of actionwithout the disadvantages of catheterization or injection. The provisionof such a route is an object of the present invention.

SUMMARY OF THE INVENTION

[0005] The present invention relates to the delivery of diazepam throughan inhalation route. Specifically, it relates to aerosols containingdiazepam that are used in inhalation therapy.

[0006] In a composition aspect of the present invention, the aerosolcomprises particles comprising at least 5 percent by weight of diazepam.Preferably, the particles comprise at least 10 percent by weight ofdiazepam. More preferably, the particles comprise at least 20 percent,30 percent, 40 percent, 50 percent, 60 percent, 70 percent, 80 percent,90 percent, 95 percent, 97 percent, 99 percent, 99.5 percent or 99.97percent by weight of diazepam.

[0007] Typically, the aerosol has a mass of at least 10 μg. Preferably,the aerosol has a mass of at least 100 μg. More preferably, the aerosolhas a mass of at least 200 μ.

[0008] Typically, the aerosol particles comprise less than 10 percent byweight of diazepam degradation products. Preferably, the particlescomprise less than 5 percent by weight of diazepam degradation products.More preferably, the particles comprise less than 2.5, 1, 0.5, 0.1 or0.03 percent by weight of diazepam degradation products.

[0009] Typically, the particles comprise less than 90 percent by weightof water. Preferably, the particles comprise less than 80 percent byweight of water. More preferably, the particles comprise less than 70percent, 60 percent, 50 percent, 40 percent, 30 percent, 20 percent, 10percent, or 5 percent by weight of water.

[0010] Typically, the aerosol has an inhalable aerosol drug mass densityof between 0.1 mg/L and 15 mg/L. Preferably, the aerosol has aninhalable aerosol drug mass density of between 0.2 mg/L and 10 mg/L.More preferably, the aerosol has an inhalable aerosol drug mass densityof between 0.5 mg/L and 8 mg/L.

[0011] Typically, the aerosol has an inhalable aerosol particle densitygreater than 10⁶ particles/mL. Preferably, the aerosol has an inhalableaerosol particle density greater than 10⁷ particles/mL. More preferably,the aerosol has an inhalable aerosol particle density greater than 10⁸particles/mL.

[0012] Typically, the aerosol particles have a mass median aerodynamicdiameter of less than 5 microns. Preferably, the particles have a massmedian aerodynamic diameter of less than 3 microns. More preferably, theparticles have a mass median aerodynamic diameter of less than 2 or 1micron(s).

[0013] Typically, the geometric standard deviation around the massmedian aerodynamic diameter of the aerosol particles is less than 3.0.Preferably, the geometric standard deviation is less than 2.5. Morepreferably, the geometric standard deviation is less than 2.1.

[0014] Typically, the aerosol is formed by heating a compositioncontaining diazepam to form a vapor and subsequently allowing the vaporto condense into an aerosol.

[0015] In a method aspect of the present invention, diazepam isdelivered to a mammal through an inhalation route. The method comprises:a) heating a composition, wherein the composition comprises at least 5percent by weight of diazepam; and, b) allowing the vapor to cool,thereby forming a condensation aerosol comprising particles, which isinhaled by the mammal. Preferably, the composition that is heatedcomprises at least 10 percent by weight of diazepam. More preferably,the composition comprises 20 percent, 30 percent, 40 percent, 50percent, 60 percent, 70 percent, 80 percent, 90 percent, 95 percent, 97percent, 99 percent, 99.5 percent, 99.9 percent or 99.97 percent byweight of diazepam.

[0016] Typically, the delivered aerosol particles comprise at least 5percent by weight of diazepam. Preferably, the particles comprise atleast 10 percent by weight of diazepam. More preferably, the particlescomprise at least 20 percent, 30 percent, 40 percent, 50 percent, 60percent, 70 percent, 80 percent, 90 percent, 95 percent, 97 percent, 99percent, 99.5 percent, 99.9 percent or 99.97 percent by weight ofdiazepam.

[0017] Typically, the condensation aerosol has a mass of at least 10 μg.Preferably, the aerosol has a mass of at least 100 μg. More preferably,the aerosol has a mass of at least 200 μ.

[0018] Typically, the delivered aerosol particles comprise less than 10percent by weight of diazepam degradation products. Preferably, theparticles comprise less than 5 percent by weight of diazepam degradationproducts. More preferably, the particles comprise less than 2.5, 1, 0.5,0.1 or 0.03 percent by weight of diazepam degradation products.

[0019] Typically, the particles comprise less than 90 percent by weightof water. Preferably, the particles comprise less than 80 percent byweight of water. More preferably, the particles comprise less than 70percent, 60 percent, 50 percent, 40 percent, 30 percent, 20 percent, 10percent, or 5 percent by weight of water.

[0020] Typically, the particles of the delivered condensation aerosolhave a mass median aerodynamic diameter of less than 5 microns.Preferably, the particles have a mass median aerodynamic diameter ofless than 3 microns. More preferably, the particles have a mass medianaerodynamic diameter of less than 2 or 1 micron(s).

[0021] Typically, the geometric standard deviation around the massmedian aerodynamic diameter of the aerosol particles is less than 3.0.Preferably, the geometric standard deviation is less than 2.5. Morepreferably, the geometric standard deviation is less than 2.1.

[0022] Typically, the delivered aerosol has an inhalable aerosol drugmass density of between 0.1 mg/L and 15 mg/L. Preferably, the aerosolhas an inhalable aerosol drug mass density of between 0.2 mg/L and 10mg/L. More preferably, the aerosol has an inhalable aerosol drug massdensity of between 0.5 mg/L and 8 mg/L.

[0023] Typically, the delivered aerosol has an inhalable aerosolparticle density greater than 10⁶ particles/mL. Preferably, the aerosolhas an inhalable aerosol particle density greater than 10⁷ particles/mL.More preferably, the aerosol has an inhalable aerosol particle densitygreater than 10⁸ particles/mL.

[0024] Typically, the rate of inhalable aerosol particle formation ofthe delivered condensation aerosol is greater than 10⁸ particles persecond. Preferably, the aerosol is formed at a rate greater than 10⁹inhalable particles per second. More preferably, the aerosol is formedat a rate greater than 10¹⁰ inhalable particles per second.

[0025] Typically, the delivered aerosol is formed at a rate greater than0.25 mg/second. Preferably, the aerosol is formed at a rate greater than0.5 mg/second. More preferably, the aerosol is formed at a rate greaterthan 1 or 2 mg/second.

[0026] Typically, the condensation aerosol delivers between 0.2 mg and20 mg of diazepam to the mammal in a single inspiration. Preferably,between 0.35 mg and 10 mg of diazepam are delivered to the mammal in asingle inspiration. More preferably, between 0.5 mg and 8 mg of diazepamare delivered to the mammal in a single inspiration.

[0027] Typically, the delivered condensation aerosol results in a peakplasma concentration of diazepam in the mammal in less than 1 h.Preferably, the peak plasma concentration is reached in less than 0.5 h.More preferably, the peak plasma concentration is reached in less than0.2, 0.1, 0.05, 0.02, 0.01, or 0.005 h (arterial measurement).

[0028] Typically, the delivered condensation aerosol is used to treatanxiety.

[0029] In a kit aspect of the present invention, a kit for deliveringdiazepam through an inhalation route to a mammal is provided whichcomprises: a) a composition comprising at least 5 percent by weight ofdiazepam; and, b) a device that forms a diazepam containing aerosol fromthe composition, for inhalation by the mammal. Preferably, thecomposition comprises at least 10 percent by weight of diazepam. Morepreferably, the composition comprises at least 20 percent, 30 percent,40 percent, 50 percent, 60 percent, 70 percent, 80 percent, 90 percent,95 percent, 97 percent, 99 percent, 99.5 percent, 99.9 percent or 99.97percent by weight of diazepam.

[0030] Typically, the device contained in the kit comprises: a) anelement for heating the diazepam composition to form a vapor; b) anelement allowing the vapor to cool to form an aerosol; and, c) anelement permitting the mammal to inhale the aerosol.

BRIEF DESCRIPTION OF THE FIGURES

[0031]FIG. 1 shows a device used to deliver diazepam containing aerosolsto a mammal through an inhalation route.

DETAILED DESCRIPTION OF THE INVENTION

[0032] Definitions

[0033] “Aerodynamic diameter” of a given particle refers to the diameterof a spherical droplet with a density of 1 g/mL (the density of water)that has the same settling velocity as the given particle.

[0034] “Aerosol” refers to a suspension of solid or liquid particles ina gas.

[0035] “Aerosol drug mass density” refers to the mass of diazepam perunit volume of aerosol.

[0036] “Aerosol mass density” refers to the mass of particulate matterper unit volume of aerosol.

[0037] “Aerosol particle density” refers to the number of particles perunit volume of aerosol.

[0038] “Condensation aerosol” refers to an aerosol formed byvaporization of a substance followed by condensation of the substanceinto an aerosol.

[0039] “Diazepam” refers to7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one.

[0040] “Diazepam” degradation product refers to a compound resultingfrom a chemical modification of diazepam. The modification, for example,can be the result of a thermally or photochemically induced reaction.Such reactions include, without limitation, oxidation and hydrolysis.Examples of products from such reactions include C₁₆H₁₅N₂O₂Cl (iminehydrolysis) and C₁₄H₁₂NOCl (imine hydrolysis followed by amidehydrolysis).

[0041] “Inhalable aerosol drug mass density” refers to the aerosol drugmass density produced by an inhalation device and delivered into atypical patient tidal volume.

[0042] “Inhalable aerosol mass density” refers to the aerosol massdensity produced by an inhalation device and delivered into a typicalpatient tidal volume.

[0043] “Inhalable aerosol particle density” refers to the aerosolparticle density of particles of size between 100 nm and 5 micronsproduced by an inhalation device and delivered into a typical patienttidal volume.

[0044] “Mass median aerodynamic diameter” or “MMAD” of an aerosol refersto the aerodynamic diameter for which half the particulate mass of theaerosol is contributed by particles with an aerodynamic diameter largerthan the MMAD and half by particles with an aerodynamic diameter smallerthan the MMAD.

[0045] “Rate of aerosol formation” refers to the mass of aerosolizedparticulate matter produced by an inhalation device per unit time.

[0046] “Rate of inhalable aerosol particle formation” refers to thenumber of particles of size between 100 nm and 5 microns produced by aninhalation device per unit time.

[0047] “Rate of drug aerosol formation” refers to the mass ofaerosolized diazepam produced by an inhalation device per unit time.

[0048] “Settling velocity” refers to the terminal velocity of an aerosolparticle undergoing gravitational settling in air.

[0049] “Typical patient tidal volume” refers to 1 L for an adult patientand 15 mL/kg for a pediatric patient.

[0050] “Vapor” refers to a gas, and “vapor phase” refers to a gas phase.The term “thermal vapor” refers to a vapor phase, aerosol, or mixture ofaerosol-vapor phases, formed preferably by heating.

[0051] Formation of Diazepam Containing Aerosols

[0052] Any suitable method is used to form the aerosols of the presentinvention. A preferred method, however, involves heating a compositioncomprising diazepam to produce a vapor, followed by cooling of the vaporsuch that it condenses to provide a diazepam comprising aerosol(condensation aerosol). The composition is heated in one of two forms:as pure active compound (i.e., pure diazepam); or, as a mixture ofactive compound and a pharmaceutically acceptable excipient. Typically,the composition is heated on a solid support.

[0053] Pharmaceutically acceptable excipients are either volatile ornonvolatile. Volatile excipients, when heated, are concurrentlyvolatilized, aerosolized and inhaled with diazepam. Classes of suchexcipients are known in the art and include, without limitation,gaseous, supercritical fluid, liquid and solid solvents. The followingis a list of exemplary carriers within the classes: water; terpenes,such as menthol; alcohols, such as ethanol, propylene glycol, glyceroland other similar alcohols; dimethylformamide; dimethylacetamide; wax;supercritical carbon dioxide; dry ice; and mixtures thereof.

[0054] Solid supports on which the composition is heated are of avariety of shapes. Examples of such shapes include, without limitation,cylinders of less than 1.0 mm in diameter, boxes of less than 1.0 mmthickness and virtually any shape permeated by small (e.g., less than1.0 mm-sized) pores. Preferably, solid supports provide a large surfaceto volume ratio (e.g., greater than 100 per meter) and a large surfaceto mass ratio (e.g., greater than 1 cm² per gram).

[0055] A solid support of one shape can also be transformed into anothershape with different properties. For example, a flat sheet of 0.25 mmthickness has a surface to volume ratio of approximately 8,000 permeter. Rolling the sheet into a hollow cylinder of 1 cm diameterproduces a support that retains the high surface to mass ratio of theoriginal sheet but has a lower surface to volume ratio (about 400 permeter).

[0056] A number of different materials are used to construct the solidsupports. Classes of such materials include, without limitation, metals,inorganic materials, carbonaceous materials and polymers. The followingare examples of the material classes: aluminum, silver, gold, stainlesssteel, copper and tungsten; silica, glass, silicon and alumina;graphite, porous carbons, carbon yarns and carbon felts;polytetrafluoroethylene and polyethylene glycol. Combinations ofmaterials and coated variants of materials are used as well.

[0057] Where aluminum is used as a solid support, aluminum foil is asuitable material. Examples of silica, alumina and silicon basedmaterials include amphorous silica S-5631 (Sigma, St. Louis, Mo.),BCR171 (an alumina of defined surface area greater than 2 m²/g fromAldrich, St. Louis, Mo.) and a silicon wafer as used in thesemiconductor industry. Carbon yarns and felts are available fromAmerican Kynol, Inc., New York, N.Y. Chromatography resins such asoctadecycl silane chemically bonded to porous silica are exemplarycoated variants of silica.

[0058] The heating of the diazepam compositions is performed using anysuitable method. Examples of methods by which heat can be generatedinclude the following: passage of current through an electricalresistance element; absorption of electromagnetic radiation, such asmicrowave or laser light; and, exothermic chemical reactions, such asexothermic salvation, hydration of pyrophoric materials and oxidation ofcombustible materials.

[0059] Delivery of Diazepam Containing Aerosols

[0060] Diazepam containing aerosols of the present invention aredelivered to a mammal using an inhalation device. Where the aerosol is acondensation aerosol, the device has at least three elements: an elementfor heating a diazepam containing composition to form a vapor; anelement allowing the vapor to cool, thereby providing a condensationaerosol; and, an element permitting the mammal to inhale the aerosol.Various suitable heating methods are described above. The element thatallows cooling is, in it simplest form, an inert passageway linking theheating means to the inhalation means. The element permitting inhalationis an aerosol exit portal that forms a connection between the coolingelement and the mammal's respiratory system.

[0061] One device used to deliver diazepam containing aerosol isdescribed in reference to FIG. 1. Delivery device 100 has a proximal end102 and a distal end 104, a heating module 106, a power source 108, anda mouthpiece 110. A diazepam composition is deposited on a surface 112of heating module 106. Upon activation of a user activated switch 114,power source 108 initiates heating of heating module 106 (e.g, throughignition of combustible fuel or passage of current through a resistiveheating element). The diazepam composition volatilizes due to theheating of heating module 106 and condenses to form a condensationaerosol prior to reaching the mouthpiece 110 at the proximal end of thedevice 102. Air flow traveling from the device distal end 104 to themouthpiece 110 carries the condensation aerosol to the mouthpiece 110,where it is inhaled by the mammal.

[0062] Devices, if desired, contain a variety of components tofacilitate the delivery of diazepam containing aerosols. For instance,the device may include any component known in the art to control thetiming of drug aerosolization relative to inhalation (e.g.,breath-actuation), to provide feedback to patients on the rate and/orvolume of inhalation, to prevent excessive use (i.e., “lock-out”feature), to prevent use by unauthorized individuals, and/or to recorddosing histories.

[0063] Dosage of Diazepam Containing Aerosols

[0064] For the management of anxiety disorders and relief of anxietysymptoms, diazepam is given orally at strengths of 2 mg to 10 mg, 2 to 4times daily. As an aerosol, 0.2 mg to 20 mg of diazepam is generallyprovided per inspiration for the same indication. A typical dosage of adiazepam aerosol is either administered as a single inhalation or as aseries of inhalations taken within an hour or less. Where the drug isadministered as a series of inhalations, a different amount may bedelivered in each inhalation.

[0065] One can determine the appropriate dose of a diazepam containingaerosol to treat a particular condition using methods such as animalexperiments and a dose-finding (Phase I/II) clinical trial. One animalexperiment involves measuring plasma concentrations of drug in an animalafter its exposure to the aerosol. Mammals such as dogs or primates aretypically used in such studies, since their respiratory systems aresimilar to that of a human. Initial dose levels for testing in humansare generally less than or equal to the dose in the mammal model thatresulted in plasma drug levels associated with a therapeutic effect inhumans. Dose escalation in humans is then performed, until either anoptimal therapeutic response is obtained or a dose-limiting toxicity isencountered.

[0066] Analysis of Diazepam Containing Aerosols

[0067] Purity of a diazepam containing aerosol is determined using anumber of methods, examples of which are described in Sekine et al.,Journal of Forensic Science 32:1271-1280 (1987) and Martin et al.,Journal of Analytic Toxicology 13:158-162 (1989). One method involvesforming the aerosol in a device through which a gas flow (e.g., airflow) is maintained, generally at a rate between 0.4 and 60 L/min. Thegas flow carries the aerosol into one or more traps. After isolationfrom the trap, the aerosol is subjected to an analytical technique, suchas gas or liquid chromatography, that permits a determination ofcomposition purity.

[0068] A variety of different traps are used for aerosol collection. Thefollowing list contains examples of such traps: filters; glass wool;impingers; solvent traps, such as dry ice-cooled ethanol, methanol,acetone and dichloromethane traps at various pH values; syringes thatsample the aerosol; empty, low-pressure (e.g., vacuum) containers intowhich the aerosol is drawn; and, empty containers that fully surroundand enclose the aerosol generating device. Where a solid such as glasswool is used, it is typically extracted with a solvent such as ethanol.The solvent extract is subjected to analysis rather than the solid(i.e., glass wool) itself. Where a syringe or container is used, thecontainer is similarly extracted with a solvent.

[0069] The gas or liquid chromatograph discussed above contains adetection system (i.e., detector). Such detection systems are well knownin the art and include, for example, flame ionization, photon absorptionand mass spectrometry detectors. An advantage of a mass spectrometrydetector is that it can be used to determine the structure of diazepamdegradation products.

[0070] Particle size distribution of a diazepam containing aerosol isdetermined using any suitable method in the art (e.g., cascadeimpaction). An Andersen Eight Stage Non-viable Cascade Impactor(Andersen Instruments, Smyrna, Ga.) linked to a furnace tube by a mockthroat (USP throat, Andersen Instruments, Smyrna, Ga.) is one systemused for cascade impaction studies.

[0071] Inhalable aerosol mass density is determined, for example, bydelivering a drug-containing aerosol into a confined chamber via aninhalation device and measuring the mass collected in the chamber.Typically, the aerosol is drawn into the chamber by having a pressuregradient between the device and the chamber, wherein the chamber is atlower pressure than the device. The volume of the chamber shouldapproximate the tidal volume of an inhaling patient.

[0072] Inhalable aerosol drug mass density is determined, for example,by delivering a drug-containing aerosol into a confined chamber via aninhalation device and measuring the amount of active drug compoundcollected in the chamber. Typically, the aerosol is drawn into thechamber by having a pressure gradient between the device and thechamber, wherein the chamber is at lower pressure than the device. Thevolume of the chamber should approximate the tidal volume of an inhalingpatient. The amount of active drug compound collected in the chamber isdetermined by extracting the chamber, conducting chromatographicanalysis of the extract and comparing the results of the chromatographicanalysis to those of a standard containing known amounts of drug.

[0073] Inhalable aerosol particle density is determined, for example, bydelivering aerosol phase drug into a confined chamber via an inhalationdevice and measuring the number of particles of given size collected inthe chamber. The number of particles of a given size may be directlymeasured based on the light-scattering properties of the particles.Alternatively, the number of particles of a given size may be determinedby measuring the mass of particles within the given size range andcalculating the number of particles based on the mass as follows: Totalnumber of particles=Sum (from size range 1 to size range N) of number ofparticles in each size range. Number of particles in a given sizerange=Mass in the size range/Mass of a typical particle in the sizerange. Mass of a typical particle in a given size range=π*D³*φ/6, whereD is a typical particle diameter in the size range (generally, the meanof the boundary MMADs defining the size range) in microns, φ is theparticle density (in g/mL) and mass is given in units of picograms(g⁻¹²).

[0074] Rate of inhalable aerosol particle formation is determined, forexample, by delivering aerosol phase drug into a confined chamber via aninhalation device. The delivery is for a set period of time (e.g., 3 s),and the number of particles of a given size collected in the chamber isdetermined as outlined above. The rate of particle formation is equal tothe number of 100 nm to 5 micron particles collected divided by theduration of the collection time.

[0075] Rate of aerosol formation is determined, for example, bydelivering aerosol phase drug into a confined chamber via an inhalationdevice. The delivery is for a set period of time (e.g., 3 s), and themass of particulate matter collected is determined by weighing theconfined chamber before and after the delivery of the particulatematter. The rate of aerosol formation is equal to the increase in massin the chamber divided by the duration of the collection time.Alternatively, where a change in mass of the delivery device orcomponent thereof can only occur through release of the aerosol phaseparticulate matter, the mass of particulate matter may be equated withthe mass lost from the device or component during the delivery of theaerosol. In this case, the rate of aerosol formation is equal to thedecrease in mass of the device or component during the delivery eventdivided by the duration of the delivery event.

[0076] Rate of drug aerosol formation is determined, for example, bydelivering a diazepam containing aerosol into a confined chamber via aninhalation device over a set period of time (e.g., 3 s). Where theaerosol is pure diazepam, the amount of drug collected in the chamber ismeasured as described above. The rate of drug aerosol formation is equalto the amount of diazepam collected in the chamber divided by theduration of the collection time. Where the diazepam containing aerosolcomprises a pharmaceutically acceptable excipient, multiplying the rateof aerosol formation by the percentage of diazepam in the aerosolprovides the rate of drug aerosol formation.

[0077] Utility of Diazepam Containing Aerosols

[0078] The following are, without limitation, typical indications fordiazepam aerosols: moderate and severe anxiety disorders and symptoms ofanxiety; panic attacks and situational anxiety; acute alcoholwithdrawal; muscle spasm; insomnia; and, nausea.

[0079] The following examples are meant to illustrate, rather thanlimit, the present invention.

[0080] Diazepam was purchased from Sigma (www.sigma-aldrich.com).

EXAMPLE 1 Volatilization of Diazepam

[0081] Diazepam (10.0 mg) in 120 μL dichloromethane was coated onto acircular piece of aluminum foil (10 cm in diameter). The dichloromethanewas allowed to evaporate. The aluminum foil was secured onto a 100 mm×50mm petridish using parafilm. After cooling the glass bottom of thepetridish with dry ice, the aluminum side of the apparatus was placed ona hot plate at 240° C. for 10 s. The apparatus was removed from the hotplate and allowed to cool. Acetonitrile was injected through thealuminum foil onto the inside of the glass surface using a 3 mL syringe.The acetonitrile solution was concentrated and analyzed by highperformance liquid chromatography with UV absorbance detection at 225 nmlight, which indicated that the volatilized material was at least 99.9%pure.

EXAMPLE 2 Volatilization of Diazepam Using a Halogen Bulb Heat Source

[0082] A solution of 5.3 mg diazepam in 120 μL dichloromethane wascoated on a 3 cm×8 cm piece of aluminum foil. The dichloromethane wasallowed to evaporate. The coated foil was wrapped around a 300 watthalogen tube (Feit Electric Company, Pico Rivera, Calif.), which wasinserted into a glass tube sealed at one end with a rubber stopper.Running 40 V of alternating current (driven by line power controlled bya variac) through the bulb for 17 s afforded diazepam thermal vapor(including diazepam aerosol), which collected on the glass tube walls.Reverse-phase HPLC analysis with detection by absorption of 225 nm lightshowed the collected material to be at least 99.9% pure diazepam.

EXAMPLE 3 Particle Size, Particle Density, and Rate of InhalableParticle Formation of Diazepam Aerosol

[0083] A solution of 18.2 mg diazepam in 200 μL dichloromethane wasspread out in a thin layer on the central portion of a 4 cm×9 cm sheetof aluminum foil. The dichloromethane was allowed to evaporate. Thealuminum foil was wrapped around a 300 watt halogen tube, which wasinserted into a T-shaped glass tube. One of the openings of the tube wassealed with a rubber stopper, another was loosely covered with the endof the halogen tube, and the third was connected to a 1 liter, 3-neckglass flask. The glass flask was further connected to a large pistoncapable of drawing 1.1 liters of air through the flask. Alternatingcurrent was run through the halogen bulb by application of 90 V using avariac connected to 110 V line power. Within 1 s, an aerosol appearedand was drawn into the 1 L flask by use of the piston, with collectionof the aerosol terminated after 6 s. The aerosol was analyzed byconnecting the 1 L flask to an eight-stage Andersen non-viable cascadeimpactor. Results are shown in table 1. MMAD of the collected aerosolwas 1.74 microns with a geometric standard deviation of 2.02. Also shownin table 1 is the number of particles collected on the various stages ofthe cascade impactor, given by the mass collected on the stage dividedby the mass of a typical particle trapped on that stage. The mass of asingle particle of diameter D is given by the volume of the particle,πD³/6, multiplied by the density of the drug (taken to be 1 g/cm³). Theinhalable aerosol particle density is the sum of the numbers ofparticles collected on impactor stages 3 to 8 divided by the collectionvolume of 1 L, giving an inhalable aerosol particle density of 5.87×10¹⁰particles/L (5.87×10⁷ particles/mL). The rate of inhalable aerosolparticle formation is the sum of the numbers of particles collected onimpactor stages 3 through 8 divided by the formation time of 6 s, givinga rate of inhalable aerosol particle formation of 9.8×10⁹particles/second. TABLE 1 Determination of the characteristics of adiazepam condensation aerosol by cascade impaction using an Andersen8-stage non-viable cascade impactor run at 1 cubic foot per minute airflow. Mass Particle size Average particle collected Number of Stagerange (microns) size (microns) (mg) particles 0  9.0-10.0 9.5 0.2 4.46 ×10⁵ 1 5.8-9.0 7.4 0 0 2 4.7-5.8 5.25 0.3 3.96 × 10⁶ 3 3.3-4.7 4.0 0.82.39 × 10⁷ 4 2.1-3.3 2.7 1.4 1.36 × 10⁸ 5 1.1-2.1 1.6 2.8 1.31 × 10⁹ 60.7-1.1 0.9 1.3 3.41 × 10⁹ 7 0.4-0.7 0.55 0.4 6.11 × 10⁹ 8   0-0.4 0.20.2  4.77 × 10¹⁰

EXAMPLE 4 Drug Mass Density and Rate of Drug Aerosol Formation ofDiazepam Aerosol

[0084] A solution of 5.1 mg diazepam in 200 μL dichloromethane wasspread out in a thin layer on the central portion of a 4 cm×9 cm sheetof aluminum foil. The dichloromethane was allowed to evaporate. Thealuminum foil was wrapped around a 300 watt halogen tube, which wasinserted into a T-shaped glass tube. One of the openings of the tube wassealed with a rubber stopper, another was loosely covered with the endof the halogen tube, and the third was connected to a 1 liter, 3-neckglass flask. The glass flask was further connected to a large pistoncapable of drawing 1.1 liters of air through the flask. Alternatingcurrent was run through the halogen bulb by application of 90 V using avariac connected to 110 V line power. Within seconds, an aerosolappeared and was drawn into the 1 L flask by use of the piston, withformation of the aerosol terminated after 6 s. The aerosol was allowedto sediment onto the walls of the 1 L flask for approximately 30minutes. The flask was then extracted with dichloromethane and theextract analyzed by HPLC with detection by light absorption at 225 nm.Comparison with standards containing known amounts of diazepam revealedthat 3.8 mg of >99% pure diazepam had been collected in the flask,resulting in an aerosol drug mass density of 3.8 mg/L. The aluminum foilupon which the diazepam had previously been coated was weighed followingthe experiment. Of the 5.1 mg originally coated on the aluminum, all ofthe material was found to have aerosolized in the 6 s time period,implying a rate of drug aerosol formation of 0.85 mg/s.

1. A composition for delivery of diazepam consisting of a condensationaerosol a) formed by volatilizing a thin layer of diazepam on a solidsupport, having the surface texture of a metal foil, to a temperaturesufficient to produce a heated vapor of diazepam and condensing theheated vapor of diazepam to form condensation aerosol particles, b)wherein said condensation aerosol particles are characterized by lessthan 5% diazepam degradation products, and c) the condensation aerosolhas an MMAD of less than 3 microns.
 2. The composition according toclaim 1, wherein the aerosol particles are formed at a rate of at least10⁹ particles per second.
 3. The composition according to claim 2,wherein the aerosol particles are formed at a rate of at least 10¹⁰particles per second.
 4. The composition according to claim 1, whereinsaid condensation aerosol particles are characterized by less than 2.5%diazepam degradation products.
 5. A method of producing diazepam in anaerosol form comprising: a. heating a thin layer of diazepam on a solidsupport, having the surface texture of a metal foil, to a temperaturesufficient to volatilize the diazepam to form a heated vapor of thediazepam, and b. during said heating, passing air through the heatedvapor to produce aerosol particles of the diazepam comprising less than5% diazepam degradation products, and an aerosol having an MMAD of lessthan 3 microns.
 6. The method according to claim 5, wherein the aerosolparticles are formed at a rate of greater than 10⁹ particles per second.7. The method according to claim 6, wherein the aerosol particles areformed at a rate of greater than 10¹⁰ particles per second.
 8. Themethod according to claim 5, wherein said aerosol particles are compriseless than 2.5% diazepam degradation products.